Hypertrophic scarring is a major clinical problem characterized by excessive fibrosis. In several treatment strategies reduced fibrosis and scarring appears connected to a reduction in force at the wound site. However, the underlying mechanisms responsible remain unclear. Multiscale mechanical interactions (MMI) could be important and ultimately deterministic of the fibrogenesis that controls scar phenotype in a healed surgical wound. MMI develop from the interplay between the geometry, structure, and organization of the clot, internal cell tractions, and external constraints of the wound. Recent work by the PI suggests that remodeling in an in vitro setting is strongly influenced by MMI that combine to produce a pattern of fibrin and ECM alignment. The initial pattern that forms controls both how macroscopic forces are distributed through the microstructure to the cells and how replacement ECM will be organized. MMI could also play an important role in wound healing. In strategies that involve changing the mechanical environment of the wound site (e.g. stress shielding sheets, shape memory sutures, sutures with elastic gradients, and adhesives), many important variables are not optimally defined. For example, it is not clear if there is an optimal window in time for stress shielding the wound site, how much or what kind of force should be applied, whether the amount of force should change over time, or how these parameters should change with anatomical site, wound size, and shape. To answer these questions, a multiscale perspective involving MMI is required. The experiments and modeling detailed here will help provide this new and important perspective. Aim 1 tests the hypothesis that MMI control fibrogenesis during the remodeling process in an in vitro setting. Here we will observe and quantify fibroblast- ECM interactions and remodeling in fibrin gels as a function of initial fibrin alignment, cell spatial distribution, mechanical load, and geometry, and then assesses how changing the loading environment at later time points can positively alter ECM remodeling to reduce scar. Completion of this aim will provide new knowledge on directing MMI to reduce scar formation and on developing new interventions that could be used to optimize healing. Aim 2 develops a computational multiscale mechanical model of the wound site that is strongly linked to in vitro microstructural and mechanical data collected from fibrin gels. Completion of this aim will provide a detailed view of load transmission, fiber reorganization, and the mechanical microenvironment in fibrin gels. The long-term goal is to use this work as a basis for developing predictive models of wound healing that will allow clinicians to devise patient-specific strategies to minimize scar formation. These models could then be used to recommend an optimized regimen of location and time dependent compression and tension that is delivered by patient-specific devices/dressings based on wound parameters such as location, geometry, and age. The proposed project therefore can significantly impact clinical management of scar formation.